Interferon-β Plays a Detrimental Role in Experimental Traumatic Brain Injury by Enhancing Neuroinflammation That Drives Chronic Neurodegeneration

Abstract

DNA damage and type I interferons (IFNs) contribute to inflammatory responses after traumatic brain injury (TBI). TBI-induced activation of microglia and peripherally-derived inflammatory macrophages may lead to tissue damage and neurological deficits. Here, we investigated the role of IFN-␤ in secondary injury after TBI using a controlled cortical impact model in adult male IFN-␤-deficient (IFN-␤ Ϫ/Ϫ) mice and assessed post-traumatic neuroinflammatory responses, neuropathology, and long-term functional recovery. TBI increased expression of DNA sensors cyclic GMP-AMP synthase and stimulator of interferon genes in wild-type (WT) mice. IFN-␤ and other IFN-related and neuroinflammatory genes were also upregulated early and persistently after TBI. TBI increased expression of proinflammatory mediators in the cortex and hippocampus of WT mice, whereas levels were mitigated in IFN-␤ Ϫ/Ϫ mice. Moreover, long-term microglia activation, motor, and cognitive function impairments were decreased in IFN-␤ Ϫ/Ϫ TBI mice compared with their injured WT counterparts; improved neurological recovery was associated with reduced lesion volume and hippocampal neurodegeneration in IFN-␤ Ϫ/Ϫ mice. Continuous central administration of a neutralizing antibody to the IFN-␣/␤ receptor (IFNAR) for 3 d, beginning 30 min post-injury, reversed early cognitive impairments in TBI mice and led to transient improvements in motor function. However, anti-IFNAR treatment did not improve long-term functional recovery or decrease TBI neuropathology at 28 d post-injury. In summary, TBI induces a robust neuroinflammatory response that is associated with increased expression of IFN-␤ and other IFN-related genes. Inhibition of IFN-␤ reduces post-traumatic neuroinflammation and neurodegeneration, resulting in improved neurological recovery. Thus, IFN-␤ may be a potential therapeutic target for TBI.

The Ubiquitin E3 Ligase Parkin Inhibits Innate Antiviral Immunity Through K48-Linked Polyubiquitination of RIG-I and MDA5

“…When neurodegenerative diseases occur in the central nervous system, mitochondrial DNA can activate the innate immunity and cause neuroinflammation ( 47 ). Type I IFN contribute to the inflammatory response during normal aging and in age-related neurodegenerative disorders ( 48 – 51 ). In our study, we found that PINK1 and Parkin mediated mitophagy can inhibit the response and antiviral immunity of type I IFN, and these results may suggest that loss of functional PINK1 and Parkin may increase IFN production and drive the pathology of neurodegeneration.…”

HMGB1-Mediated Neuroinflammatory Responses in Brain Injuries: Potential Mechanisms and Therapeutic Opportunities

“…All the components of this feedback loop lead to aggravation of neuronal dysfunction and tissue loss [36]. More precisely, TBI-mediated phenomena of secondary injury include enduring neuroinflammation over time that may contribute to chronic neurological impairment [37]. The delayed nature of neuroinflammation reflects the possibility of a therapeutic window for intervention against the progressive brain tissue damage and the subsequent improvement of functional recovery after injury [38].…”

The Complexity of the cGAS-STING Pathway in CNS Pathologies

“…Type-I interferons (IFNs) have been strongly implicated in the progression of neuroinflammation in a host of central nervous system (CNS) pathologies including Alzheimer’s disease ( Taylor et al, 2014 ; Minter et al, 2016 ; Roy et al, 2020 ), Parkinson’s disease ( Main et al, 2016 ; Qin et al, 2016 ), traumatic brain injury ( Karve et al, 2016 ; Barrett et al, 2020 ) and amyotrophic lateral sclerosis (ALS) ( Oakes et al, 2017 ; Shelkovnikova et al, 2019 ). However, the role of the type-I IFN upstream regulator, the stimulator of interferon genes (STING), in driving this response in the CNS remains largely unknown.…”